Neuromodulation targets pathological not physiological beta bursts during gait in Parkinson's disease.

Freezing of gait (FOG) is a devastating axial motor symptom in Parkinson's disease (PD) leading to falls, institutionalization, and even death. The response of FOG to dopaminergic medication and deep brain stimulation (DBS) is complex, variable, and yet to be optimized. Fundamental gaps in the knowledge of the underlying neurobiomechanical mechanisms of FOG render this symptom one of the unsolved challenges in the treatment of PD. Subcortical neural mechanisms of gait impairment and FOG in PD are largely unknown due to the challenge of accessing deep brain circuitry and measuring neural signals in real time in freely-moving subjects. Additionally, there is a lack of gait tasks that reliably elicit FOG. Since FOG is episodic, we hypothesized that dynamic features of subthalamic (STN) beta oscillations, or beta bursts, may contribute to the Freezer phenotype in PD during gait tasks that elicit FOG. We also investigated whether STN DBS at 60 Hz or 140 Hz affected beta burst dynamics and gait impairment differently in Freezers and Non-Freezers. Synchronized STN local field potentials, from an implanted, sensing neurostimulator (Activa® PC + S, Medtronic, Inc.), and gait kinematics were recorded in 12 PD subjects, off-medication during forward walking and stepping-in-place tasks under the following randomly presented conditions: NO, 60 Hz, and 140 Hz DBS. Prolonged movement band beta burst durations differentiated Freezers from Non-Freezers, were a pathological neural feature of FOG and were shortened during DBS which improved gait. Normal gait parameters, accompanied by shorter bursts in Non-Freezers, were unchanged during DBS. The difference between the mean burst duration between hemispheres (STNs) of all individuals strongly correlated with the difference in stride time between their legs but there was no correlation between mean burst duration of each STN and stride time of the contralateral leg, suggesting an interaction between hemispheres influences gait. These results suggest that prolonged STN beta burst durations measured during gait is an important biomarker for FOG and that STN DBS modulated long not short burst durations, thereby acting to restore physiological sensorimotor information processing, while improving gait.

Subthalamic neural entropy is a feature of freezing of gait in freely moving people with Parkinson's disease.

The goal of this study was to investigate subthalamic (STN) neural features of Freezers and Non-Freezers with Parkinson's disease (PD), while freely walking without freezing of gait (FOG) and during periods of FOG, which were better elicited during a novel turning and barrier gait task than during forward walking. METHODS: Synchronous STN local field potentials (LFPs), shank angular velocities, and ground reaction forces were measured in fourteen PD subjects (eight Freezers) off medication, OFF deep brain stimulation (DBS), using an investigative, implanted, sensing neurostimulator (Activa® PC+S, Medtronic, Inc.). Tasks included standing still, instrumented forward walking, stepping in place on dual forceplates, and instrumented walking through a turning and barrier course. RESULTS: During locomotion without FOG, Freezers showed lower beta (13-30Hz) power (P=0.036) and greater beta Sample Entropy (P=0.032), than Non-Freezers, as well as greater gait asymmetry and arrhythmicity (P<0.05 for both). No differences in alpha/beta power and/or entropy were evident at rest. During periods of FOG, Freezers showed greater alpha (8-12Hz) Sample Entropy (P<0.001) than during walking without FOG. CONCLUSIONS: A novel turning and barrier course was superior to FW in eliciting FOG. Greater unpredictability in subthalamic beta rhythms was evident during stepping without freezing episodes in Freezers compared to Non-Freezers, whereas greater unpredictability in alpha rhythms was evident in Freezers during FOG. Non-linear analysis of dynamic neural signals during gait in freely moving people with PD may yield greater insight into the pathophysiology of FOG; whether the increases in STN entropy are causative or compensatory remains to be determined. Some beta LFP power may be useful for rhythmic, symmetric gait and DBS parameters, which completely attenuate STN beta power may worsen rather than improve FOG.

Transcutaneous Afferent Patterned Stimulation Therapy Reduces Hand Tremor for One Hour in Essential Tremor Patients.

Essential tremor (ET) patients often experience hand tremor that impairs daily activities. Non-invasive electrical stimulation of median and radial nerves in the wrist using a recently developed therapy called transcutaneous afferent patterned stimulation (TAPS) has been shown to provide symptomatic tremor relief in ET patients and improve patients' ability to perform functional tasks, but the duration of tremor reduction is unknown. In this single-arm, open-label study, fifteen ET patients performed four hand tremor-specific tasks (postural hold, spiral drawing, finger-to-nose reach, and pouring) from the Fahn-Tolosa-Marin Clinical Rating Scale (FTM-CRS) prior to, during, and 0, 30, and 60 min following TAPS. At each time point, tremor severity was visually rated according to the FTM-CRS and simultaneously measured by wrist-worn accelerometers. The duration of tremor reduction was assessed using (1) improvement in the mean FTM-CRS score across all four tasks relative to baseline, and (2) reduction in accelerometer-measured tremor power relative to baseline for each task. Patients were labeled as having at least 60 min of therapeutic benefit from TAPS with respect to each specified metric if all three (i.e., 0, 30, and 60 min) post-therapy measurements were better than that metric's baseline value. The mean FTM-CRS scores improved for at least 60 min beyond the end of TAPS for 80% (12 of 15, p = 4.6e-9) of patients. Similarly, for each assessed task, tremor power improved for at least 60 min beyond the end of TAPS for over 70% of patients. The postural hold task had the largest reduction in tremor power (median 5.9-fold peak reduction in tremor power) and had at least 60 min of improvement relative to baseline beyond the end of TAPS therapy for 73% (11 of 15, p = 9.8e-8) of patients. Clinical ratings of tremor severity were correlated to simultaneously recorded accelerometer-measured tremor power (r = 0.33-0.76 across the four tasks), suggesting tremor power is a valid, objective tremor assessment metric that can be used to track tremor symptoms outside the clinic. These results suggest TAPS can provide reductions in upper limb tremor symptoms for at least 1 h post-therapy in some patients, which may improve patients' ability to perform tasks of daily living.

The turning and barrier course reveals gait parameters for detecting freezing of gait and measuring the efficacy of deep brain stimulation.

Freezing of gait (FOG) is a devastating motor symptom of Parkinson's disease that leads to falls, reduced mobility, and decreased quality of life. Reliably eliciting FOG has been difficult in the clinical setting, which has limited discovery of pathophysiology and/or documentation of the efficacy of treatments, such as different frequencies of subthalamic deep brain stimulation (STN DBS). In this study we validated an instrumented gait task, the turning and barrier course (TBC), with the international standard FOG questionnaire question 3 (FOG-Q3, r = 0.74, p < 0.001). The TBC is easily assembled and mimics real-life environments that elicit FOG. People with Parkinson's disease who experience FOG (freezers) spent more time freezing during the TBC compared to during forward walking (p = 0.007). Freezers also exhibited greater arrhythmicity during non-freezing gait when performing the TBC compared to forward walking (p = 0.006); this difference in gait arrhythmicity between tasks was not detected in non-freezers or controls. Freezers' non-freezing gait was more arrhythmic than that of non-freezers or controls during all walking tasks (p < 0.05). A logistic regression model determined that a combination of gait arrhythmicity, stride time, shank angular range, and asymmetry had the greatest probability of classifying a step as FOG (area under receiver operating characteristic curve = 0.754). Freezers' percent time freezing and non-freezing gait arrhythmicity decreased, and their shank angular velocity increased in the TBC during both 60 Hz and 140 Hz STN DBS (p < 0.05) to non-freezer values. The TBC is a standardized tool for eliciting FOG and demonstrating the efficacy of 60 Hz and 140 Hz STN DBS for gait impairment and FOG. The TBC revealed gait parameters that differentiated freezers from non-freezers and best predicted FOG; these may serve as relevant control variables for closed loop neurostimulation for FOG in Parkinson's disease.